Studies to identify the cellular receptor for dengue virus currently involve screening a panel of monoclonal antibodies directed against the cell surface of the mosquito cell line, C6/36. 562 antibody producing, hybridoma cell lines were selected after fusion of splenocytes purified from a mouse immunized with cell membrane preps from C6/36 cells. Supernatants from these cells were used in a virus blocking assay. Inhibition of infectivity was measured by pretreating cells with monoclonal supernatants, inoculating cells with DEN2 virus in the presence of antibody, and measuring virus antigen production at 48 hours post inoculation using an ELISA format. In the primary screen, "positive" monoclonals were scored for the ability of the supernatant to inhibit DEN2 infection by greater than 10% as compared to untreated cells. Stringent screening procedures using the original positives has shown that six of the supernatants show the ability to reproducibly inhibit DEN2 infectivity. The pathogenic flaviviruses are mosquito or tick vector-borne. Clinical syndromes caused by these viruses fall into 3 very different categories: fever-arthralgia-rash, hepatitis and gastroenteritis, and encephalitis. Among mosquito-borne pathogenic flaviviruses, there exists exquisite species specificity for a given vector. This diversity of pathogenicity and vector specificity exists despite the fact that the flavivirus envelope glycoprotein (E), the major antigen of the virus and the viral attachment protein, is highly conserved in both sequence and predicted conformation. One possible explanation for the phenomenon is that virus attachment is mediated by variable regions in E interacting with species-specific cellular receptors in the midgut epithelium of mosquitoes and with human host tissue-specific receptors. Identification of a set of such receptors and determination of the mode of their interaction with virus will help to explain the pathogenesis of disease caused by flaviviruses and may suggest a mechanism for prevention or therapy.